The effect of base sequence and solvent conditions on the solution structures of oligomeric and polymeric DNA molecules will be determined by high field 1H and 31P NMR as well as by CD and uv spectroscopy. Microcalorimetric techniques will then be used to thermodynamically characterize the helix-to-coil and helix-to-helix transitions of these structures. Batch and titration calorimetry will be used to isothermally study conformational transitions induced by salt, pH and metal ions. Differential scanning calorimetry will be used to investigate thermally-induced conformational changes under varying solution conditions. These experiments will provide a complete, model-independent thermodynamic profile of the interactions which determine conformation and thus allow the prediction of the most stable conformation as a function of base sequence and solution conditions. In other words, the results of these experiments will allow us to construct a phase diagram for DNA polymorphism in which the conformational states are mapped as a function of base sequence and solution conditions. Considering the potential role of conformational heterogeneity as a mechanism for selective, local control of events such as protein-nucleic acid interactions, drug-DNA binidng, gene expression, and DNA packing, an ability to predict local conformational preferences in DNA polymers is of the utmost importance. The calorimetric experiments described in this proposal are designed to provide the thermodynamic data required to establish this predictive ability so that sequences favoring specific structural forms can be identified and correlated with particular functional roles.